The RGD (arginine-glycine-aspartic acid) is a key recognition sequence of cell surface receptors in many cell adhesion-promoting extracellular matrix proteins, including fibronectin, vitronectin, laminin, some collagens, and many others (Ruoslahti, 2003). Integrins, a large family of cell surface receptors, bind to extracellular matrix at the RGD sequence. Roughly one third of integrins use the RGD sequence as their recognition site; the others recognize other sequences. The RGD sequence also mediates the binding of platelets to fibrinogen in blood clotting. RGD peptides and peptidomimetics can be used to modulate integrin activity. These compounds are also useful in delivering therapeutic and diagnostic compounds to sites where integrins are active. A vast drug discovery effort centers on the RGD and related peptides and a number of RGD-based drugs are already on the market or in clinical trials (Ruoslahti, 2003; 2004).
Tumors, tissue regeneration, and inflammation induce the growth of new blood vessels from pre-existing ones. This process, angiogenesis, is a vital requirement for wound healing as the formation of new blood vessels allows a variety of mediators nutrients, and oxygen to reach the healing tissue (Marin 1997, Singer & Clark 1999, Falanga 2006, Folkman 2006). Newly formed blood vessels differ in structure from preexisting vasculature. Such differences have been extensively characterized by comparing tumor vasculature to normal vessels (Ruoslahti, 2002). Angiogenic vessels in non-malignant tissues and in pre-malignant lesions share markers with tumor vessels, but distinct markers also exist (Hoffman et al., 2003; Joyce et al., 2003).
A major hurdle to advances in treating cancer is the relative lack of agents that can selectively target the cancer while sparing normal tissue. For example, radiation therapy and surgery, which generally are localized treatments, can cause substantial damage to normal tissue in the treatment field, resulting in scarring and loss of normal tissue. Chemotherapy, in comparison, which generally is administered systemically, can cause substantial damage to organs such as the bone marrow, mucosae, skin and small intestine, which undergo rapid cell turnover and continuous cell division. As a result, undesirable side effects such as nausea, loss of hair and drop in blood cell count often occur when a cancer patient is treated intravenously with a chemotherapeutic drug. Such undesirable side effects can limit the amount of a drug that can be safely administered, thereby hampering survival rate and impacting the quality of patient life. Thus, there is a need for new therapeutic strategies for selectively targeting tumors to increase the efficacy of diagnosis and treatment, and to reduce the side effects associated with systemic therapy. The present invention satisfies this need by providing molecules that selectively home to tumors, and which are suitable for selectively targeting drugs, gene therapy vectors or other agents to the appropriate tissue. Related advantages also are provided.